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OLIGOMERIC Aβ ALTERS TRANSPORT OF GluR2 mRNA
by
Chiara Ferrari
A Thesis Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
MASTER OF SCIENCE
(EXPERIMENTAL AND MOLECULAR PATHOLOGY)
May 2012
Copyright 2012 Chiara Ferrari

Alzheimer’s disease (AD) is characterized by loss of memory and learning deficits caused by synaptic damage secondary to toxic oligomeric beta-amyloid (oAβ) deposition. Several glutamate receptors regulate transmission at the synapse, including the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, composed of the four subunits, GluR1-4. The GluR2 subunit has been found to contribute to Ca2+ regulation by rendering the AMPA receptor impermeable to it. oAβ may directly affect synaptic function by interacting with the AMPA receptor, which was found to have a binding site for Aβ (Tozaki et al., 2002). ❧ GluR2 mRNA is thought to be transported to the synapse via the dendrite where it is locally translated (Grooms et al., 2006). We hypothesize that oAβ causes a shift in the transport of GluR2 mRNA, resulting in aberrant local expression of the receptor. Since Ca2+ dysregulation is thought to be involved in the pathogenesis of AD, the effect of oAβ on GluR2 may directly contribute to synaptic dysfunction. ❧ Using organotypic rat cortical cultures exposed to nanomolar levels of oAβ for 7 to 21 days, we examined the distribution of GluR2 subunit protein and GluR2 mRNA using fluorescent immunohistochemical and in situ hybridization techniques. In control (untreated) tissue, the GluR2 subunit colocalizes with the scaffold protein PSD-95, indicating its presence at the postsynaptic endings, whereas there is minimal or no colocalization in the oAβ-treated tissue. ❧ Next, we analyzed two splice variants of GluR2 mRNA: flip and flop. The distribution of GluR2 mRNA also appears to be affected by oAβ treatment. In untreated rat cortical tissue, mRNA has a diffuse appearance and is visible in the neuropil and dendritic projections, and with less frequency in the cytoplasm around the soma. In the oAβ -treated tissue, GluR2 mRNA appears to be present in lesser amounts in the neuropil, clustering mostly around the soma, and assuming a punctate appearance when visible in dendritic projections. This effect is evident in both the flip and flop splice variants after 2 weeks of oAβ treatment. ❧ Our findings suggest that oAβ may influence localization of GluR2 mRNA, inducing it to assemble into granules which remain primarily in the soma. These results suggest that oAβ may cause a shift in the transport of GluR2 mRNA, resulting in aberrant expression in the soma. These results may be an early step in the disease pathogenesis, and the consequences of this alteration may contribute to the synaptic changes.

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OLIGOMERIC Aβ ALTERS TRANSPORT OF GluR2 mRNA
by
Chiara Ferrari
A Thesis Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
MASTER OF SCIENCE
(EXPERIMENTAL AND MOLECULAR PATHOLOGY)
May 2012
Copyright 2012 Chiara Ferrari